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Review Article

Antibiotic Resistance and Treatment Options for Multidrug-Resistant Gonorrhea

Yang, Fan1,#; Yan, Jing1,#

Editor(s): van der Veen, Stijn1,2,3,⊠; Leptihn, Sebastian

Author Information
Infectious Microbes & Diseases: June 2020 - Volume 2 - Issue 2 - p 67-76
doi: 10.1097/IM9.0000000000000024
  • Open

Abstract

Introduction

Gonorrhea is the second most prevalent sexually transmitted infection globally, which is caused the human-specific gram-negative bacterium Neisseria gonorrhoeae. The World Health Organization estimates that there are annually 78–87 million new gonorrhea cases.1,2N. gonorrhoeae usually colonizes and infects the genital tract, but the rectal and oropharyngeal mucosa may also be colonized.3 In men, gonorrhea most commonly manifests as urethritis and epididymo-orchitis, while women typically develop cervicitis, which is often asymptomatic. However, untreated female infections may lead to pelvic inflammatory disease, ectopic pregnancies, and infertility.4–6 Furthermore, complicated gonococcal infections can increase the risk of human immunodeficiency virus transmission and acquisition by increasing the human immunodeficiency virus loads in the genital tract.7 In the absence of effective gonococcal vaccines, antimicrobial therapy has remained the principal for control of gonorrhea infections.

Anti-gonococcal therapy over the past century

Since the discovery of antibiotics and their application in the clinics, recommended treatments for gonorrhea have required continuous adaptation to remain efficient (Figure 1). Sulfonamides were the first effective antibiotics introduced for treatment of gonorrhea in the 1930s, but N. gonorrhoeae developed widespread resistance in the next decades.8,9 Penicillin was first advised for treatment of gonorrhea in 1943, but doses required continuous upwards adjustments and treatment failures were increasingly reported within the next decades.10 In addition, plasmids encoding TEM-type β-lactamases, which provide high-level penicillin resistance, have increasingly spread within the gonococcal populations since the late 1970s and 1980s.11 Tetracycline was introduced as alternative antimicrobial for gonococcal therapy in the 1960s, but its use was compromised by the 1980s because of the emergence of plasmid-borne high-level tetracycline resistance caused by TetM.12,13 The aminocyclitol spectinomycin became an alternative gonococcal treatment option in the early 1960s, but within several years spectinomycin resistance was detected.14 Spectinomycin remained an alternative first-line therapy until the early 1980s, after which it was disbanded due to rapid increasing resistance rates.15 Spectinomycin resistance is quite rare at the moment and; therefore, it is still recommended as alternative therapy in South-Korea and some other countries,16 but spectinomycin therapy should be used with caution due to its frequent failure to cure pharyngeal infections.17 The fluoroquinolone ciprofloxacin has been in use for gonococcal therapy since the mid-1980s, but treatment failures became increasingly common since the early 1990s and treatment doses required continuous adjustments.18–20 Resistant strains became increasingly common, initially in the Asia Pacific region and subsequently globally, and therefore ciprofloxacin was removed from treatment guidelines in most countries by the mid-2000s. Azithromycin was developed in the 1980s and commonly used for treatment of gonorrhea in many countries in the 1990s. However, azithromycin resistance rapidly evolved by the late-1990s, particularly in countries showing wide usage.21,22 Over the past decade, azithromycin has not been commonly used as first-line monotherapy, but it is generally included in a dual therapy in combination with ceftriaxone.23 However, inclusion of azithromycin in a dual therapy has come under scrutiny in recent years,24 leading to the exclusion of azithromycin from dual therapy by some countries.25 Also worryingly, high-level azithromycin-resistant N. gonorrhoeae, defined by a minimal inhibitory concentration (MIC) ≥256 mg/L, have been isolated in many countries.26–39 The cephalosporins ceftriaxone (intramuscular or intravenous), cefixime (oral), and other oral cephalosporins have been recommended for therapy since the 1990s.23,40–42 However, global susceptibility levels have been on the decline ever since, and as a result oral cephalosporins have become ineffective in many countries, particularly in the Asia Pacific region and China.39,43,44 As a result, dual therapy consisting of ceftriaxone and azithromycin has generally been recommended over the past decade in many developed countries.23,42 In recent years, confirmed treatment failures for ceftriaxone and ceftriaxone plus azithromycin dual therapy have been increasingly reported.45–51 Particularly, international transmission of the ceftriaxone-resistant FC428 clone over the past few years52–62 poses serious threats to the currently last available first-line treatments and raises the possibility of untreatable gonorrhea in the near future.

Figure 1
Figure 1:
Timeline depicting antimicrobials used for treatment of gonorrhea and occurrence of resistance. Since the introduction of sulfonamides in the 1930s, Neisseria gonorrhoeae has developed resistance against all subsequently recommended antimicrobial therapies, leading to a possible future situation where all cases of gonorrhea require screening of antimicrobial susceptibility and personalized treatment.

Gonococcal antimicrobial resistance mechanisms

N. gonorrhoeae is intrinsically resistant to numerous antimicrobials, such as vancomycin, trimethoprim, and colistin,63 and in addition has accumulated an impressive set of antimicrobial resistance mechanisms over the past century, mostly through genomic mutations.64 Only the β-lactamase (penicillinase) encoding gene blaTEM, which provides high-level resistance to penicillin11 and the tetM gene, which provides high-level resistance to tetracycline12,13 are plasmid-borne. Penicillinase-producing N. gonorrhoeae isolates are common and all express the TEM-type β-lactamase from a group of closely related plasmids, most commonly the Asian and African types.65,66 Although TEM-type β-lactamases expressed from these plasmids are not active against cephalosporins, the TEM-135 variant, which is highly abundant in gonococcal isolates from some regions,66 has the propensity to evolve into an extended-spectrum β-lactamase that is able to hydrolyze cephalosporins such as ceftriaxone and cefixime.67

One of the most important gonococcal antimicrobial resistance determinants that provides nonspecific resistance to penicillins, cephalosporins, azithromycin, tetracycline, ciprofloxacin, and other hydrophobic or amphipathic drugs is the multidrug efflux pump MtrCDE.68–73 Particularly, mutations that derepress MtrCDE, such as the adenine deletion in the promoter of mtrRCDE and the A39T or G45D polymorphisms of MtrR, have been associated with the development of multidrug resistance in N. gonorrhoeae.71,74 Also, mosaic mtrRCDE alleles acquired from Neisseria meningitidis and commensal Neisseria species appeared to contribute to multidrug resistance.75,76 Of note, activity of the MtrCDE efflux pump is essential for in vivo biological fitness and mutations that derepress this efflux pump are therefore commonly found in clinical isolates.70,71,77,78 Interestingly, targeting MtrCDE by dampening its expression has been suggested as a way to sensitize N. gonorrhoeae to currently disbanded antibiotics and possibly to antimicrobial compounds produced in the human host.70,79 Besides increasing efflux, also reducing influx through mutations in the major outer membrane porin PorB1b has been shown to increase resistance against penicillin, cephalosporins, and tetracycline. Specifically, mutations in the porin constriction zone at positions G120 and A121 to more bulky charged residues have resulted in increased resistance levels.80,81

In addition to these nonspecific resistance determinants, N. gonorrhoeae has also evolved many specific mutations in the target sites of a variety of antimicrobials, thereby reducing affinity and increasing resistance levels. Penicillins and cephalosporins target gonococcal penicillin binding protein 2 and; therefore, mutations in the penicillin binding protein 2-encoding gene penA that reduce acylation by penicillin and cephalosporins, but retain sufficient transpeptidase activity, provide increased resistance. Penicillin-resistance has most commonly been the result of an aspartate insertion at position 345,82,83 while reduced susceptibility or resistance to cephalosporins is generally associated with alanine 501 polymorphisms84 or mosaic penA alleles with up to 70 amino acid polymorphisms.43,85,86 In recent years, strains displaying high-level ceftriaxone resistance have been increasingly encountered (Table 1). These strains commonly contain mosaic penA alleles with additional A311V, T483S, T316P, and/or A501P polymorphisms.50,57,87–90 However, where the high-level ceftriaxone-resistant penA alleles 37 and 42 have remained sporadic, likely as a results of reduced biological fitness associated with these alleles,91 strains with penA allele 60 (FC428 clone) has shown global transmission.52–62 Tetracycline targets the ribosomal 30S subunit and reversibly inhibits protein synthesis and the V57M polymorphism in ribosomal protein S10, encoded by rpsJ, has been shown to confer tetracycline resistance.92 Of note, this polymorphism was present in all tested isolates from a recent study in China, indicating that it has become widely disseminated in some countries.93 Spectinomycin also targets the 30S ribosome and resistance has been the result of a C1192U mutation in 16S rRNA or by mutations in ribosomal protein S5, encoded by rpsE, namely a deletion of the valine at position 25 combined with a K26E polymorphism.94–96 Ciprofloxacin targets the DNA gyrase, consisting of GyrA and GyrB subunits, and the topoisomerase IV that consists of the ParC and ParE subunits. Ciprofloxacin resistance arises from a variety of mutations in the GyrA and ParC subunits and the exact resistance levels are determined by the specific combination of mutations.97,98 Sulfonamides target the folP-encoded enzyme dihydropteroate synthase to inhibit folic acid synthesis and gonococcal resistance can arise from a variety of folP point mutations.64 Azithromycin targets the 50S ribosomal subunit and blocks the 23S rRNA component. Resistance against azithromycin is the result from specific mutations in the target loop V of 23S rRNA. Low level azithromycin resistance is caused by a C2611T polymorphism, while high-level resistance is the result from an A2059G polymorphism.26,99 Interestingly, the 23S rRNA A2059G polymorphism improves in vivo biological fitness in a mouse model of infection,99 which might explain why this mutation has been associated with outbreak strains displaying high-level azithromycin resistance in the UK and Hawaii27,30 and why strains with this mutation have shown widespread transmission in south-east China.33,39,100 To study antimicrobial resistance patterns, ensure treatment guidelines are adequate and to obtain insight into the epidemiology of resistance mechanism, the N. gonorrhoeae sequence typing for antimicrobial resistance (https://ngstar.canada.ca) tool was recently developed, which assigns sequence types (STs) and alleles based on polymorphism in penA, mtrR, porB, ponA, gyrA, parC, and 23S rRNA.101 These N. gonorrhoeae sequence typing for antimicrobial resistance STs are now commonly used and combined with the STs assigned by the N. gonorrhoeae multiantigen sequence typing (http://ng-mast.net) and multilocus sequence typing (https://pubmlst.org/neisseria) methods.

Table 1
Table 1:
Characteristics of verified high-level ceftriaxone-resistant gonococcal isolates.

Alternative clinically approved antimicrobials

Due to the declining ceftriaxone susceptibility levels and the increasing incidence of treatment failure, alternative gonococcal therapies are urgently required. Therefore, the World Health Organization recently included N. gonorrhoeae in their priority list of multidrug-resistant bacterial pathogens to support research and development of effective drugs and therapies.102 Alternative clinically approved antibiotics offer the most rapid solution if their efficacy is deemed appropriate. For this purpose, gentamicin,103 ertapenem,93,104,105 tigecycline,93,106 fosfomycin,107 fusic acid,108,109 gemifloxacin,110 doxycycline,111 and rifampicin111 have all been investigated for their effectiveness as replacement therapy. However, based on recent comprehensive gonococcal susceptibility analyses, fosfomycin, gemifloxacin, doxycycline, and rifampicin are unlikely to be suitable as alternative therapies.93,112–115

In recent years, the best-studied alternative antimicrobial for treatment of gonorrhea has been gentamicin, which has undergone several clinical trials as part of a dual therapy and more recently also as single therapy. A multicenter trial performed in the USA over the period 2010–2012 studied the efficacy of gentamicin 240 mg intramuscularly combined with 2 g oral azithromycin for treatment of urogenital gonorrhea.116 A 100% cure rate was demonstrated in all 202 participants, which also included 10 pharyngeal and 1 rectal infections. Similar results were obtained in a recent trial performed in the Czech Republic over the period 2016–219 that studied the efficacy of 240 mg intramuscular gentamicin plus 2 g oral azithromycin for treatment of rectal and pharyngeal gonorrhea.117 All 72 patients receiving gentamicin/azithromycin (40 rectal, 17 pharyngeal, 15 rectal plus pharyngeal) were cured at follow-up, which was tested by both culture and NAAT. However, a multicenter trial performed in the UK over the period 2014–2016 that studied efficacy of 240 mg intramuscular gentamicin combined with 1 g oral azithromycin showed inferiority compared with ceftriaxone/azithromycin therapy for treatment of gonorrhea.118 Of the 292 patients included in the gentamicin/azithromycin group, only 267 were cured (91%), which compared with a 98% efficacy in the ceftriaxone/azithromycin group. Efficacy in treatment of pharyngeal infections was particularly low, with only 82 of the 102 infections (80%) being cured. Given the different azithromycin doses in these trials (2 g vs 1 g) and the contrasting results, these trials raise questions about the actual contribution of gentamicin in the gentamicin/azithromycin dual therapy, particularly for pharyngeal infections. To address this discrepancy, a recent single-center trial in the USA studied the efficacy of a single 360 mg intramuscular gentamicin dose for treatment of pharyngeal gonorrhea.119 The aim of the trial was to evaluate efficacy in 50 participants; however, it was terminated early due to the poor performance of gentamicin, since only two of the first 10 participants were actually cured. Treatment failure did not appear to be the result of gentamycin-resistant isolates, since all isolates displayed gentamicin MIC values of 4–8 mg/L. These values are in line with a recent large-scale gonococcal gentamicin susceptibility study performed over the period 2015–2016 in the USA, which showed that 71% of the 10,403 tested isolates displayed a gentamicin MIC of 8 mg/L and 24% a MIC of 4 mg/L.120 Similar gentamicin MICs were recently demonstrated in Europe, with 79% of the isolates displaying a MIC of 8 mg/L,121 while MIC values were higher in China (MIC50/MIC90 =16 mg/L)93 and lower in India122 and Malawi.123 Although official breakpoints for gentamicin have not yet been established, unofficial breakpoints have been proposed as R ≥ 32 mg/L and S ≤ 4 mg/L.124 However, based on these susceptibility criteria, the majority of isolates in the USA, Europe, and China would already be classified as intermediate susceptible, which together with the poor gentamicin efficacy in pharyngeal treatment indicates that gentamicin should be used with caution and not as a first-line therapy.

The carbapenem β-lactam ertapenem has been included in several antimicrobial susceptibility studies using collections of clinical isolates. Compared with ceftriaxone, the ertapenem MIC values were generally equal or higher.104,114,125 Although, MIC90 values for ertapenem were slightly lower them ceftriaxone MIC90 values in a recent study investigating isolates from China, which was suggested to be related with the generally higher ceftriaxone MIC values observed in that study.93 Importantly, there was a poor correlation between ceftriaxone and ertapenem MIC values, suggesting that cross-resistance between ceftriaxone and ertapenem is poor.93 Therefore, ertapenem was suggested as an alternative antimicrobial for particularly the ceftriaxone-resistant isolates. Particularly, high-level ceftriaxone-resistant isolates with penA alleles 37 (HO41)89 and 42 (F89)50,87 are still susceptible to ertapenem.105 Ertapenem has also been successfully used for treatment of gonorrhea caused by high-level ceftriaxone resistant strains, and even for strains displaying combined ceftriaxone and high-level azithromycin resistance.46,47,53 Importantly, strains containing penA allele 60 appear to still be susceptible to ertapenem,47,53,60 which therefore might serve as an alternative therapy for the internationally-spreading ceftriaxone-resistant FC428 clone. Of note, based on fractional inhibitory concentration index analyses, ertapenem and ceftriaxone do not appear to display any interactions,115 indicating that they could also be used in combination therapies.

Thus far, only a few studies have investigated susceptibility of gonococcal isolates to the glycylcycline tigecycline. Recent analysis of 504 contemporary clinical isolates from China showed that all isolates were susceptible to tigecycline (MIC ≤0.5 mg/L) and the correlation with susceptibility to tetracycline and doxycycline was poor,93 indicating that the rpsJ V57M, porB1b, and mtrR resistance determinants for tetracycline or doxycycline,92 which were highly abundant in the studied strain collection, do not provide resistance against tigecycline. Similarly, all gonococcal isolates appeared susceptible to tigecycline in two recent studies performed in Canada114 and Korea.126 Therefore, tigecycline might be an interesting antimicrobial for further evaluation of efficacy in clinical studies, possibly as part of a dual therapy, given that previous fractional inhibitory concentration index analyses indicated that tigecycline does not interact with other antibiotics.

Novel antimicrobials against gonorrhea

Even though many major pharmaceutical companies seemed to have abandoned their novel antimicrobial development pipelines due to limited success and expected profits, novel therapies are urgently required for many multidrug-resistant bacterial pathogens,127,128 including N. gonorrhoeae. Although some new therapeutic strategies, like macrophage cell therapy,129 or revived “old” strategies, like phage therapy,130 might be possible future approaches to combat multidrug-resistant gonorrhea, novel antimicrobials that are already in clinical development pipelines are likely required in the near future. Although several novel compounds with antimicrobial activity against N. gonorrhoeae have been identified in recent years,131–133 the most promising novel antimicrobials for anti-gonococcal therapy that were already tested in clinical trials are solithromycin, zoliflodacin, and gepotidacin.

The fluoroketolide solithromycin (CEM-101) is the latest class of macrolide antibiotics with high activity against a variety of Gram-positive and Gram-negative bacteria and which retained high affinity for bacterial ribosomes.134 Solithromycin displayed good activity against a collection of clinical isolates from Canada (2008–2011) and Sweden (2011) and international reference strains, with a MIC90 of 0.125–0.25 mg/L.135,136 However, isolates displaying high-level azithromycin resistance still displayed resistance against solithromycin, with MIC values of 4–32 mg/L. Therefore, solithromycin will not be a suitable alternative therapy in countries or regions with a high incidence of high-level azithromycin-resistant N. gonorrhoeae, such as China, the UK, and Hawaii.27,30,33,39,100 To test clinical efficacy for treatment of uncomplicated gonorrhea, a two-center phase 2 clinical trial was held in the USA, which included 59 participants that were given either 1200 mg (n = 28) or 1000 mg (n = 31) oral dose of solithromycin.137 Treatment was 100% effective and all participants were negative for N. gonorrhoeae at all sites of infection at follow-up. Evaluation of solithromycin susceptibility of cultures obtained from the participants indicated the all strains were susceptible to solithromycin (MIC ≤0.125 mg/L). In contrast, in a 2014–2015 phase 3 multicenter (Australia/USA) noninferiority trial comparing 1000 mg oral solithromycin with 500 mg intramuscular ceftriaxone plus 1 g oral azithromycin for treatment of uncomplicated gonorrhea in 261 patients, solithromycin was not deemed noninferior.138 Eradication of gonorrhea at all anatomical sites was only 91% in the solithromycin group versus 100% in the ceftriaxone/azithromycin group. Therefore, it was concluded that 1000 mg oral solithromycin was not a suitable alternative for treatment of gonorrhea. Importantly, susceptibility testing of cultures obtained from the patients indicated that all gonococcal isolates were susceptible to solithromycin (MIC ≤0.25 mg/L), indicating that treatment failure was not related to the incidence of high-level azithromycin-resistant strains. Overall, it still remains to be determined whether solithromycin will be a possible alternative therapy for future treatment of gonorrhea, specifically in light with the increasing incidence of high-level azithromycin-resistant isolates observed in some parts of the world.

Zoliflodacin (ETX0914, AZD0914) is a novel spiropyrimidinetrione that targets bacterial type II topoisomerases with a distinct mechanism from quinolones such as ciprofloxacin.139 Antimicrobial susceptibility of N. gonorrhoeae to zoliflodacin has been tested extensively, using strain collections from Europe,140 China,141 USA,142 Thailand, and South Africa,143 and global reference and defined multidrug-resistant strains,144 and all studies resulted in MIC90 values of 0.06–0.25 mg/L. Importantly, no cross-resistance was observed with ciprofloxacin-resistant isolates, but zoliflodacin-resistant derivatives were readily acquired on antibiotic plates and generally contained gyrB mutations at position 429 and 450.145,146 Zoliflodacin has already been evaluated for efficacy for treatment of uncomplicated gonorrhea in a multicenter phase 2 clinical trial performed in the USA over the period 2014–2015, which included 179 participants that were provided with oral zoliflodacin (2 or 3 g) or intramuscular ceftriaxone (5 mg).147 While ceftriaxone treatment resulted in 100% (28/28) cure at all anatomical sites, zoliflodacin only provided 96% cure (109/113) at the urogenital site and 68% (13/19) cure at the pharyngeal site. Therefore, it appears that zoliflodacin provides good activity for treatment of uncomplicated urogenital gonorrhea, but not for infections of the pharynx.

Gepotidacin (GSK2140944) is a novel triazaacenaphthylene antimicrobial agent that inhibits DNA topoisomerase IV and DNA gyrase through a distinct mechanism from fluoroquinolones and therefore remains active against ciprofloxacin-resistant N. gonorrhoeae, although specific parC mutations have been identified that reduced susceptibility.148,149 Studies on antimicrobial susceptibility using collections of clinical isolates and international reference strains, including multidrug- and ciprofloxacin-resistant isolates, reported MIC90 values of 0.25–1 mg/L.149–151 Gepotidacin treatment efficacy of uncomplicated gonorrhea has been determined in one phase 2 multicenter clinical trial over the period 2015–2016 in the USA/UK, which evaluated oral doses of 1500 and 3000 mg gepotidacin.152,153 Of the 106 participants, only 69 were microbiologically evaluable, which demonstrated a 96% cure rate (66/69). Importantly, all three treatment failures were caused by isolates with the highest observed MIC levels (1 mg/L), which contained ParC D86N and GyrA S91F-D95A/G polymorphisms that have been associated with ciprofloxacin resistance. Based on the higher then 95% success rate, further clinical trials are warranted, but the observed cross-resistance with ciprofloxacin-resistance determinants is of concern, particularly in populations with higher incidences of ciprofloxacin resistance, such as the Asia-Pacific region.

In conclusion, over the past century N. gonorrhoeae has developed resistance against all antimicrobials used for treatment of gonorrhea and during this process it has obtained an impressive repertoire of resistance determinants, mostly by adaptive genomic mutations in the target site of the respective antimicrobial, but also by acquisition of plasmid-mediated resistance genes and upregulation of a generic multidrug efflux pump. Efficacy of the currently last available first-line therapy, ceftriaxone, is rapidly waning and high-level ceftriaxone-resistant isolates, particularly isolates related to the FC428 clone, are increasingly encountered. Repurposing of clinically approved antimicrobials has thus far only resulted in extensive studies and clinical trials of gentamicin, but the efficacy of this drug has proven to be sub-optimal, particularly for pharyngeal infections. Also, several novel antimicrobials have been tested in clinical trials, but each of these drugs displayed some shortcomings, such as suboptimal pharyngeal efficacy and possible issues of cross-resistance with previously/currently used antimicrobials. It is important to highlight here that over the past decade all clinical trials for alternative gonorrhea therapies have been performed in the USA, UK, or Australia, while antimicrobial resistance and presence of resistance determinants is much more problematic in the Asia-Pacific region. Therefore, it is highly recommended to consider possible efficacy of alternative therapies in this region, with possible relocation of clinical trials. Overall, it seems unlikely that alternative first-line therapies for gonorrhea will become available in the near future to replace ceftriaxone when it is no longer considered adequate for first-line therapy. As for now, elevated ceftriaxone doses of 1–2 g still seem to be sufficient for gonorrhea treatment, since even in China it has remained without treatment failure.154 Also, some of the high-level ceftriaxone-resistant strains, such as the FC428 clone, appear to be more susceptible to ertapenem.47,60 Therefore, a future scenario might be that gonorrhea will require individualized treatments based on actual antimicrobial susceptibility levels determined for each isolate.

References

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Keywords:

Neisseria gonorrhoeae; antimicrobial resistance; AMR; ceftriaxone; alternative therapy

Copyright © 2020 the Author(s). Published by Wolters Kluwer Health, Inc.